In the preparation of semi-synthetic penicillin and cephalosporin antibiotics most chemical modifications are performed on .beta.-lactam substrates bearing C-6 or C-7 acylamino groups which are stable to the process conditions but are not preferred for maximum antibiotic activity. Thus, a process step common to the production of most if not all of the known clinically significant penicillins and cephalosporins is the cleavage of the C-6 or C-7 acylamino group to provide the corresponding C-6 or C-7 amino compounds which are reacylated as desired. Undoubtedly the most widely used method for cleaving penicillin and cephalosporin acylamino side chains is that wherein the C-6 or C-7 acylamino compound is first converted to the corresponding imino halide and then to an imino ether which, upon acidic hydrolysis or alcoholysis, provides the nucleus (C-6 or C-7 amino) compounds. This general method and improvements thereof have been described in a number of U.S. Patents including Nos. 3,549,628, 3,575,970, 3,697,515, 3,845,043 and 3,868,368.
A number of acid halides, especially, acid chlorides, derived from phosphorus, carbon and sulfur or their oxygen acids have been disclosed as useful for preparing the imino halide intermediates of the three-step amido cleavage process. Phosphorus oxychloride, phosphorus pentachloride, phosphorus trichloride, thionyl chloride, phosgene, oxalyl chloride and catechyl-phosphorus trichloride have, in particular, been described as suitable imino halide forming reagents. Laboratory experience has shown phosphorus pentachloride to be a preferred acid halide reagent for intermediate imino halide preparation.
Recently we have discovered a novel class of halogenating compounds derived not from phosphorus oxygen acids but from aryl esters thereof. More specifically we have discovered that selected triaryl phosphites react with equivalent amounts of chlorine or bromine to provide, initially, kinetically controlled products which, although thermodynamically unstable, can be used advantageously in many halogenation reactions, including the preparation of penicillin and cephalosporin imino halides. These novel halogenating compounds are disclosed and claimed in our co-pending U.S. application Ser. No. 8,469 filed on even date herewith.
It is an object of the present invention to provide a new process for preparing penicillin and cephalosporin imino halides.
It is a more specific object of the present invention to provide a high yielding method of preparing C-6 or C-7 imino halides of penicillin and cephalosporin respectively using novel triaryl phosphite-halogen kinetic complexes.